It is well-known that benzophenanthridine alkaloids can act as topical contact antibacterial and antifungal agents. It is also known that such activity is produced in vivo by combination of the benzophenanthridine alkaloids with potentiating agents such as mineral or organic acid salts of zinc, tin, copper, iron, aluminum or other similar complex forming metal salts or organic compounds.
A benzophenanthridine alkaloid can have one of two possible structures for its quinoline nucleus: an iminium structure or a free amine structure. The pH of the medium containing the alkaloid as well as chemical modifications can cause the alkaloid to convert from the iminium structure to a free amine structure.
Current belief holds that the iminium structure of the alkaloid has the necessary configuration and ionicity for transport across microorganism membranes and for chemical interaction with the biological system. As a corollary, the free amine alkaloid is thought to be inactive as an antibacterial or antifungal agent.
It is also thought that the physical character of the free amine alkaloid may contribute to its lack of activity. The free amine alkaloid is often, but not always, substantially insoluble in aqueous media because of its hydrophobic structure. However, hydrophilic derivatives of the free amine alkaloid can be prepared and these derivatives have greater solubility in aqueous solutions.
Based upon the understanding of the biological activity of benzophenanthridine alkaloids as conveyed by the art, it is expected that these alkaloids would have no biological activity at an approximately neutral pH or above. The predominant structure of the alkaloid at this higher pH is the free amine. The biological activity, however, is believed to be associated with the iminium structure, which is the predominant structure at the lower pH. Consequently, it is surprising to find according to the present invention that the benzophenanthridine alkaloids have increased biological activity at such higher pH's and very little activity at lower pH's which cause the iminium structure to be predominant. Moreover, it is surprising to find that benzophenanthridine alkaloid derivatives having the free base structure are also biologically active.
It is an object of the invention, therefore, to develop systemic and local pharmaceutical compositions that contain the benzophenanthridine alkaloid as the free amine. A further object is the development of appropriate parameters to maintain the benzophenanthridine alkaloid as the free amine.